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Inhibition of rat cerebellar nitric oxide synthase by 7‐nitro indazole and related substituted indazoles
Author(s) -
Babbedge R.C.,
BlandWard P.A.,
Hart S.L.,
Moore P.K.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13796.x
Subject(s) - indazole , nitric oxide synthase , chemistry , nitro , nitric oxide , nitroarginine , cerebellum , stereochemistry , medicine , endocrinology , biology , organic chemistry , alkyl
1 7‐Nitro indazole (7‐NI) produces potent inhibition of rat cerebellar nitric oxide synthase (NOS) with an IC 50 of 0.9 ± 0.1 μ m ( n = 6). NOS activity is dependent on the presence of both exogenous CaCl 2 and NADPH. The inhibitory potency of 7‐NI remained unaltered in the presence of different concentrations of either CaCl 2 (0.75–7.5 m m ) or NADPH (0.05–5.0 m m ). 2 Kinetic (Lineweaver‐Burke) analysis of the effect of 7‐NI on rat cerebellar NOS revealed that inhibition was of a competitive nature with a K i value of 5.6 μ m . The K m of cerebellar NOS with respect to L‐arginine was 2.5 μ m . 3 The following indazole derivatives (IC 50 values shown in parentheses, all n = 6) caused concentration‐related inhibition of rat cerebellar NOS in vitro : 6‐nitro indazole (31.6 ± 3.4 μ m ), 5‐nitro indazole (47.3 ± 2.3 μ m ), 3‐chloro indazole (100.0 ± 5.5 μ m ), 3‐chloro 5‐nitro indazole (158.4 ± 2.1 μ m ) and indazole (177.8 ± 2.1 μ m ). The IC 50 values for 5‐amino indazole, 6‐amino indazole and 6‐sulphanilimido indazole were in excess of 1 m m ; 3‐indazolinone was inactive. 4 7‐NI (10 mg kg −1 ) administered i.p. to rats produced 60 min thereafter a significant inhibition of NOS activity in cerebellum (31.1 ± 3.2%, n = 6), cerebral cortex (38.2 ± 5.6%, n = 6), hippocampus (37.0 ± 2.8%, n = 6) and adrenal gland (23.7 ± 3.0%, n = 6). NOS activity in olfactory bulb and stomach fundus were unchanged. 5 These results indicate that 7‐NI is a potent and competitive inhibitor of rat brain NOS in vitro and also inhibits NOS in different brain regions and in the adrenal gland in vivo . Inhibition of NOS is a characteristic property of the indazole nucleus. Nitration of the indazole ring at positions 5, 6 and 7 results in a graded increase in inhibitory potency. Indazole‐based inhibitors of NOS may prove useful tools with which to evaluate the biological roles of nitric oxide in the central nervous system.